Tuberculosis (TB) is the leading cause of death among HIV-infected adults in Africa and other parts of the world. Recently, the potential for widespread transmission of multidrug and extensively drug resistant (MDR and XDR) TB among HIV-infected persons in hospitals and other congregate settings has been reported, and may undermine advances in survival achieved by increasing global access to antiretroviral therapy. However, epidemiological and laboratory observations on the infectiousness of MDR-TB patients and the transmissibility and virulence of MDR-M. tuberculosis strains have been conflicting. Some data suggest TB/HIV patients are more infectious than HIV-uninfected/TB patients, while others suggest the opposite. Other work suggests that MDR-TB strains are heterogeneous in transmissibility and virulence as a consequence of genetic mutations responsible for drug resistance. Greater understanding of the airborne transmission of MDR-TB strains among HIV co-infected persons in clinical settings is essential to achieving better transmission control. In this career development proposal, the applicant plans to test the hypothesis that HIV co-infected MDR-TB patients are potentially less infectious than HIV-uninfected MDR-TB patients by comparing their production of culturable cough aerosols and by comparing the infection rate of exposed sentinel guinea pigs after controlling for cough aerosol production. He will also test the hypothesis that MDR- TB strains of attenuated virulence are preferentially associated with HIV co-infected MDR-TB patients compared to HIV-uninfected patients by examining the histopathology of infected guinea pigs exposed to both groups. He will conduct the proposed work with HIV-infected and HIV-uninfected MDR-TB patients in South Africa and will further develop proficiency with the use of an aerosol exposed guinea pig model of TB. He also proposes to learn microbiologic, genetic fingerprinting, and cough aerosol sampling techniques to achieve his research goals. With the support of his mentors and collaborators, he will pursue a rigorous research training program to become an independent clinical and translational investigator on MDR-M. tuberculosis virulence and the effect of HIV on the spread of MDR-TB. RELEVANCE: MDR-M. tuberculosis transmission threatens global TB control, especially in populations where HIV co-infection is prevelant. Improved understanding of how pathogen and host factors influence MDR-M. tuberculosis transmission is essential to reducing the spread of MDR-TB to individuals with HIV co-infection.